Heterogeneity of ATP‐Sensitive K+ Channels in Cardiac Myocytes: Enrichment at the Intercalated Disk

Abstract

Ventricular KATP channels link intracellular energy metabolism to membrane excitability and contractility. We identified plakoglobin (PG) and plakophilin‐2 (PKP2) as KATP channel associated proteins and investigated whether the association of KATP channel subunits with junctional proteins translates to heterogeneous subcellular distribution within a cardiac myocyte. Co‐immunoprecipitation experiments confirmed physical interaction between KATP channels and PKP2 and PG in rat heart. Immunolocalization experiments demonstrated that KATP channel subunits are expressed at a higher density at the intercalated disk (ICD) in hearts, where they colocalized with PKP2 and PG. Super‐resolution microscopy demonstrate that KATP channels are clustered within nanometer distances from junctional proteins. The local KATP channel density was larger at the cell end when compared to local currents recorded from the cell's center. The KATP channel unitary conductance, block by MgATP and activation by MgADP did not differ between these two locations. Whole‐cell KATP channel current density was ~40% smaller in myocytes from mice haploinsufficient for PKP2. Experiments with excised patches demonstrated that the regional heterogeneity of KATP channels was absent in the PKP2 deficient mice, but the KATP channel unitary conductance and nucleotide sensitivities remained unaltered. Our data demonstrate heterogeneity of KATP channel distribution within a cardiac myocyte. The higher KATP channel density at the ICD implies a possible role at the intercellular junctions during cardiac ischemia. Funding from NIH HL085820.